ADMA, subclinical changes and atrial fibrillation in the general population Meike Ramuschkat, Sebastian Appelbaum, Dorothee Atzler, Tanja Zeller, Christoph Bauer, Francisco M. Ojeda, Christoph R. Sinning, Boris Hoffmann, Karl J. Lackner, Rainer H. B¨oger, Philipp S. Wild, Thomas M¨unzel, Stefan Blankenberg, Edzard Schwedhelm, Renate B. Schnabel PII: DOI: Reference:
S0167-5273(15)01163-8 doi: 10.1016/j.ijcard.2015.05.102 IJCA 20572
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
15 February 2015 11 May 2015 17 May 2015
Please cite this article as: Ramuschkat Meike, Appelbaum Sebastian, Atzler Dorothee, Zeller Tanja, Bauer Christoph, Ojeda Francisco M., Sinning Christoph R., Hoffmann Boris, Lackner Karl J., B¨oger Rainer H., Wild Philipp S., M¨ unzel Thomas, Blankenberg Stefan, Schwedhelm Edzard, Schnabel Renate B., ADMA, subclinical changes and atrial fibrillation in the general population, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.05.102
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT ADMA, subclinical changes and atrial fibrillation in the general population
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Meike Ramuschkat2,11, MD; Sebastian Appelbaum1,4,11, BA; Dorothee Atzler3,4,10,11, PhD; Tanja Zeller1,4,11, PhD; Christoph Bauer1,11; Francisco M. Ojeda1,11, PhD; Christoph R. Sinning1,11, MD; Boris Hoffmann2,11, MD; Karl J. Lackner8,11, MD; Rainer H Böger3,4,11, MD; Philipp S. Wild4,5,6.7,11, MD, MSc; Thomas Münzel5,6,11, MD, FAHA; Stefan Blankenberg1,4,11, MD; Edzard Schwedhelm3,4,11, PhD; Renate B. Schnabel1,4,11, MD, MSc for the Gutenberg Health Study investigators 1
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PT
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Department of General and Interventional Cardiology, University Heart Center HamburgEppendorf, Germany 2 Department of Cardiology and Electrophysiology, University Heart Center HamburgEppendorf, Germany 3 Department of Clinical Pharmacology and Toxicology, University Medical Center HamburgEppendorf, Hamburg, Germany 4 DZHK (Deutsches Zentrum fuer Herz-Kreislauf-Forschung e.V.), partner site Hamburg/Kiel/Luebeck, Germany 5 Center for Cardiovascular research (DZHK), Partner Site Rhein/Main, Germany 6 Department of Medicine 2 7 Center of Thrombosis and Hemostasis 8 University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Germany 9 Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center Mainz, Germany (PSW) 10 Department of Cardiovascular Medicine, University of Oxford, UK 11 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
AC
Corresponding author: Renate B. Schnabel, MD, MSc; University Heart Center, Department of General and Interventional Cardiology, Martinistr. 52, 20246 Hamburg, Germany; Phone: +49-1522-2816064, Fax: +49 404 7410 40163, E-mail: [email protected]
Acknowledgement of grant support: This study was supported by the Stiftung Pathobiochemie of the Deutsche Vereinte Gesellschaft für Klinische Chemie und Laboratoriumsmedizin e.V. The Gutenberg Health Study is funded through “Stiftung Rheinland Pfalz für Innovation” (AZ 961-386261/733), the research programs “Wissen schafft Zukunft” and “Center for Translational Vascular Biology (CTVB)” of the Johannes GutenbergUniversity of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems. Conflict of interest: None of the authors have any conflict of interest. Key words: ADMA; L-arginine derivatives; atrial fibrillation; population-based cohort
ACCEPTED MANUSCRIPT
ADMA – subclinical changes and atrial fibrillation
ABSTRACT Background-Pathways of oxidative stress, nitric oxide bioavailability and L-arginine
PT
derivatives are hypothesized to be related to atrial fibrillation (AF). Circulating methylated Larginine metabolites can be assessed in the general population and may show an
SC RI
association with AF.
Methods-We determined L-arginine and its metabolites asymmetric dimethylarginine (ADMA), L-Nω-monomethylarginine (NMMA) and symmetric dimethylarginine (SDMA) in the
NU
population-based Gutenberg Health Study (n=5000), mean age 55±11 years, 51% men, in association with clinical variables of AF such as electrocardiographic and echocardiographic
MA
measures and manifest AF.
Results-Individuals with AF (N=161), 71% men, were older, mean age 64.9±8.3 years. In
ED
Bonferroni-corrected multivariable-adjusted regression analyses we observed moderate inverse associations for L-arginine, SDMA, and L-arginine/ADMA ratio with ventricular heart
PT
rate, and for L-arginine and L-arginine/ADMA ratio with QTc interval. L-arginine was
CE
correlated with QRS duration. In echocardiographic analyses, SDMA was related to left atrial diameter and deceleration time, ADMA and NMMA were correlated with left ventricular mass.
AC
ADMA (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.11-1-32; p=0.013) and NMMA (OR 1.17, 95% CI 1.09-1.26, p=0.014) were related to prevalent AF. Larginine/ADMA ratio was inversely associated (OR 0.8, 95% CI 0.71-0.90, p=0.0082). Results were similar after adjustment for creatinine. Conclusions-In our large, population-based cohort, we observed moderate associations of L-arginine metabolites and intermediate electrocardiographic and echocardiographic variables and AF. Our findings support further investigations to define the role of L-arginine derivatives in AF and their clinical utility.
Page 2 of 25
ACCEPTED MANUSCRIPT
ADMA – subclinical changes and atrial fibrillation INTRODUCTION The pathophysiological background of common atrial fibrillation (AF) is not well established despite its increasing prevalence in the general population and significant public health
PT
burden [1, 2]. Local and systemic signs of oxidative stress are pertinent to AF [3, 4].
SC RI
Myofibrillar energetics and function may be impaired, e.g. cardiac creatine kinase is redox sensitive and its oxidative damage contributes to atrial contractile dysfunction. High oxidative burden induces redox-responsive signaling pathways including NF-κB that lead to atrial and
NU
ventricular remodeling [5]. Two enzymes central to nitric oxide (NO) bioavailability are myocardial nicotinamide adenine dinucleotide phosphate oxidase and the endothelial nitric
MA
oxide synthase (eNOS). NO is produced from its precursor L-arginine. The dysfunction of the two enzymes with uncoupling of eNOS is responsible for the generation of reactive oxygen
dimethylarginine
(ADMA),
ED
species in atria of patients with AF [6]. The L-arginine derivatives asymmetric symmetric
dimethylarginine
(SDMA)
and
L-Nω-
PT
monomethylarginine (NMMA) are endogenous compounds of protein metabolism. ADMA is elevated as a result of oxidative protein damage of ADMA degrading enzymes and
CE
competitively inhibits NO synthesis with diverse detrimental effects on vasculature and organ function. Oxidative stress increases the activity of arginine methylating enzymes resulting in
AC
increased ADMA concentrations. ADMA perpetuates eNOS uncoupling [7]. Moreover, in healthy humans ADMA induces an elevation in blood pressure and arterial stiffness which both lead to an increased afterload and, secondarily, to left ventricular hypertrophy [8, 9]. These vascular and arterial changes are known to be associated with AF [10, 11]. Methylated L-arginine metabolites have been related to echocardiographic parameters in patients with chronic systolic heart failure and ADMA predicts outcome in dilated cardiomyopathy conditions that predispose to AF [12-14]. In small studies it could be demonstrated that ADMA plasma concentrations are elevated in individuals with AF and may be associated with adverse outcome [15, 16]. In this context, we hypothesized that L-arginine derivatives are related to AF in the general population. To better understand the relation of Larginine derivatives to AF, we further investigated their association with clinical variables, i.e. Page 3 of 25
ACCEPTED MANUSCRIPT
ADMA – subclinical changes and atrial fibrillation electrocardiographic and modern echocardiographic variables in a large, contemporary cohort.
PT
MATERIALS AND METHODS
SC RI
Study participants
The current data of this study are based on the first 5000 individuals enrolled in the Gutenberg Health Study. The cohort consists of a randomly selected population-based
NU
sample of European descent incepted in 2007 at the Department of Medicine 2, University Medical Center Mainz. Study participants are enrolled within 10-year age strata from 35-74
MA
years. In clinical examination information on cardiovascular risk factors were collected based on a computer-assisted standardized interview. Anthropometric measures and non-invasive
ED
cardiovascular function testing were performed. Smoking status was categorized into the subgroups of non-smokers (never smokers and former smokers) and current smokers.
PT
Diabetes was diagnosed if the participant reported a physician diagnosis of diabetes and/or a fasting blood glucose concentration of ≥126mg/dL (minimum 8-hour fast) or a blood glucose
CE
level of ≥200mg/dL at any time was measured on site. Dyslipidemia was defined based on a physician´s diagnosis and/or an LDL/HDL ratio of >3.5. Hypertension was defined by anti-
AC
hypertensive drug treatment and/or a mean systolic blood pressure of ≥140mmHg and/or a mean diastolic blood pressure of ≥90mmHg. A history of cardiovascular disease implicated self-reported myocardial infarction, stroke, prevalent coronary heart disease and heart failure. Heart failure was determined by clinical aspects (New York Heart Association classification, heart failure medication) and echocardiographic examination (left ventricular ejection fraction
S0167-5273(15)01163-8 doi: 10.1016/j.ijcard.2015.05.102 IJCA 20572
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
15 February 2015 11 May 2015 17 May 2015
Please cite this article as: Ramuschkat Meike, Appelbaum Sebastian, Atzler Dorothee, Zeller Tanja, Bauer Christoph, Ojeda Francisco M., Sinning Christoph R., Hoffmann Boris, Lackner Karl J., B¨oger Rainer H., Wild Philipp S., M¨ unzel Thomas, Blankenberg Stefan, Schwedhelm Edzard, Schnabel Renate B., ADMA, subclinical changes and atrial fibrillation in the general population, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.05.102
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT ADMA, subclinical changes and atrial fibrillation in the general population
SC RI
PT
Meike Ramuschkat2,11, MD; Sebastian Appelbaum1,4,11, BA; Dorothee Atzler3,4,10,11, PhD; Tanja Zeller1,4,11, PhD; Christoph Bauer1,11; Francisco M. Ojeda1,11, PhD; Christoph R. Sinning1,11, MD; Boris Hoffmann2,11, MD; Karl J. Lackner8,11, MD; Rainer H Böger3,4,11, MD; Philipp S. Wild4,5,6.7,11, MD, MSc; Thomas Münzel5,6,11, MD, FAHA; Stefan Blankenberg1,4,11, MD; Edzard Schwedhelm3,4,11, PhD; Renate B. Schnabel1,4,11, MD, MSc for the Gutenberg Health Study investigators 1
CE
PT
ED
MA
NU
Department of General and Interventional Cardiology, University Heart Center HamburgEppendorf, Germany 2 Department of Cardiology and Electrophysiology, University Heart Center HamburgEppendorf, Germany 3 Department of Clinical Pharmacology and Toxicology, University Medical Center HamburgEppendorf, Hamburg, Germany 4 DZHK (Deutsches Zentrum fuer Herz-Kreislauf-Forschung e.V.), partner site Hamburg/Kiel/Luebeck, Germany 5 Center for Cardiovascular research (DZHK), Partner Site Rhein/Main, Germany 6 Department of Medicine 2 7 Center of Thrombosis and Hemostasis 8 University Medical Center of the Johannes Gutenberg-University Mainz, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Germany 9 Preventive Cardiology and Preventive Medicine, Department of Medicine 2, University Medical Center Mainz, Germany (PSW) 10 Department of Cardiovascular Medicine, University of Oxford, UK 11 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
AC
Corresponding author: Renate B. Schnabel, MD, MSc; University Heart Center, Department of General and Interventional Cardiology, Martinistr. 52, 20246 Hamburg, Germany; Phone: +49-1522-2816064, Fax: +49 404 7410 40163, E-mail: [email protected]
Acknowledgement of grant support: This study was supported by the Stiftung Pathobiochemie of the Deutsche Vereinte Gesellschaft für Klinische Chemie und Laboratoriumsmedizin e.V. The Gutenberg Health Study is funded through “Stiftung Rheinland Pfalz für Innovation” (AZ 961-386261/733), the research programs “Wissen schafft Zukunft” and “Center for Translational Vascular Biology (CTVB)” of the Johannes GutenbergUniversity of Mainz and its contract with Boehringer Ingelheim and PHILIPS Medical Systems. Conflict of interest: None of the authors have any conflict of interest. Key words: ADMA; L-arginine derivatives; atrial fibrillation; population-based cohort
ACCEPTED MANUSCRIPT
ADMA – subclinical changes and atrial fibrillation
ABSTRACT Background-Pathways of oxidative stress, nitric oxide bioavailability and L-arginine
PT
derivatives are hypothesized to be related to atrial fibrillation (AF). Circulating methylated Larginine metabolites can be assessed in the general population and may show an
SC RI
association with AF.
Methods-We determined L-arginine and its metabolites asymmetric dimethylarginine (ADMA), L-Nω-monomethylarginine (NMMA) and symmetric dimethylarginine (SDMA) in the
NU
population-based Gutenberg Health Study (n=5000), mean age 55±11 years, 51% men, in association with clinical variables of AF such as electrocardiographic and echocardiographic
MA
measures and manifest AF.
Results-Individuals with AF (N=161), 71% men, were older, mean age 64.9±8.3 years. In
ED
Bonferroni-corrected multivariable-adjusted regression analyses we observed moderate inverse associations for L-arginine, SDMA, and L-arginine/ADMA ratio with ventricular heart
PT
rate, and for L-arginine and L-arginine/ADMA ratio with QTc interval. L-arginine was
CE
correlated with QRS duration. In echocardiographic analyses, SDMA was related to left atrial diameter and deceleration time, ADMA and NMMA were correlated with left ventricular mass.
AC
ADMA (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.11-1-32; p=0.013) and NMMA (OR 1.17, 95% CI 1.09-1.26, p=0.014) were related to prevalent AF. Larginine/ADMA ratio was inversely associated (OR 0.8, 95% CI 0.71-0.90, p=0.0082). Results were similar after adjustment for creatinine. Conclusions-In our large, population-based cohort, we observed moderate associations of L-arginine metabolites and intermediate electrocardiographic and echocardiographic variables and AF. Our findings support further investigations to define the role of L-arginine derivatives in AF and their clinical utility.
Page 2 of 25
ACCEPTED MANUSCRIPT
ADMA – subclinical changes and atrial fibrillation INTRODUCTION The pathophysiological background of common atrial fibrillation (AF) is not well established despite its increasing prevalence in the general population and significant public health
PT
burden [1, 2]. Local and systemic signs of oxidative stress are pertinent to AF [3, 4].
SC RI
Myofibrillar energetics and function may be impaired, e.g. cardiac creatine kinase is redox sensitive and its oxidative damage contributes to atrial contractile dysfunction. High oxidative burden induces redox-responsive signaling pathways including NF-κB that lead to atrial and
NU
ventricular remodeling [5]. Two enzymes central to nitric oxide (NO) bioavailability are myocardial nicotinamide adenine dinucleotide phosphate oxidase and the endothelial nitric
MA
oxide synthase (eNOS). NO is produced from its precursor L-arginine. The dysfunction of the two enzymes with uncoupling of eNOS is responsible for the generation of reactive oxygen
dimethylarginine
(ADMA),
ED
species in atria of patients with AF [6]. The L-arginine derivatives asymmetric symmetric
dimethylarginine
(SDMA)
and
L-Nω-
PT
monomethylarginine (NMMA) are endogenous compounds of protein metabolism. ADMA is elevated as a result of oxidative protein damage of ADMA degrading enzymes and
CE
competitively inhibits NO synthesis with diverse detrimental effects on vasculature and organ function. Oxidative stress increases the activity of arginine methylating enzymes resulting in
AC
increased ADMA concentrations. ADMA perpetuates eNOS uncoupling [7]. Moreover, in healthy humans ADMA induces an elevation in blood pressure and arterial stiffness which both lead to an increased afterload and, secondarily, to left ventricular hypertrophy [8, 9]. These vascular and arterial changes are known to be associated with AF [10, 11]. Methylated L-arginine metabolites have been related to echocardiographic parameters in patients with chronic systolic heart failure and ADMA predicts outcome in dilated cardiomyopathy conditions that predispose to AF [12-14]. In small studies it could be demonstrated that ADMA plasma concentrations are elevated in individuals with AF and may be associated with adverse outcome [15, 16]. In this context, we hypothesized that L-arginine derivatives are related to AF in the general population. To better understand the relation of Larginine derivatives to AF, we further investigated their association with clinical variables, i.e. Page 3 of 25
ACCEPTED MANUSCRIPT
ADMA – subclinical changes and atrial fibrillation electrocardiographic and modern echocardiographic variables in a large, contemporary cohort.
PT
MATERIALS AND METHODS
SC RI
Study participants
The current data of this study are based on the first 5000 individuals enrolled in the Gutenberg Health Study. The cohort consists of a randomly selected population-based
NU
sample of European descent incepted in 2007 at the Department of Medicine 2, University Medical Center Mainz. Study participants are enrolled within 10-year age strata from 35-74
MA
years. In clinical examination information on cardiovascular risk factors were collected based on a computer-assisted standardized interview. Anthropometric measures and non-invasive
ED
cardiovascular function testing were performed. Smoking status was categorized into the subgroups of non-smokers (never smokers and former smokers) and current smokers.
PT
Diabetes was diagnosed if the participant reported a physician diagnosis of diabetes and/or a fasting blood glucose concentration of ≥126mg/dL (minimum 8-hour fast) or a blood glucose
CE
level of ≥200mg/dL at any time was measured on site. Dyslipidemia was defined based on a physician´s diagnosis and/or an LDL/HDL ratio of >3.5. Hypertension was defined by anti-
AC
hypertensive drug treatment and/or a mean systolic blood pressure of ≥140mmHg and/or a mean diastolic blood pressure of ≥90mmHg. A history of cardiovascular disease implicated self-reported myocardial infarction, stroke, prevalent coronary heart disease and heart failure. Heart failure was determined by clinical aspects (New York Heart Association classification, heart failure medication) and echocardiographic examination (left ventricular ejection fraction
